issues of mechanism of ageing

Mechanisms of Ageing and Development

Vol.125, issue 2, pp.93-151. Feb. 2004

Biological and social predictors of immune senescence in the aged primate

Christopher L. Coe^,

Harlow Center for Biological Psychology, University of Wisconsin, 22 North Charter Street, Madison, WI 53715, USA

Available online 7 December 2003.

Abstract

The transition to geriatric status occurs at around 20 years of age in monkeys after which there is typically a decline in immune responses. However, the loss in immune vigor may be quite dissociated from chronological age in some of these long-lived animals. The degree to which natural killer (NK) cell activity is sustained in aged monkeys has proven to be a valuable prognostic of ultimate health and longevity. Another useful biomarker of cellular aging in the monkey is interleukin-6 (IL-6) release. For example, when endothelial cell cultures were generated from cerebral blood vessels, those derived from aged donors produced significantly more IL-6 in response to IL-1, LPS, and hypoxia. Despite this evidence of intrinsic aging, we have found that immune responses in old animals are quite responsive to contemporaneous conditions, including changes in housing or the first onset of illness. Indeed, these changes, especially the pathological processes associated with disease, may promote many age-related immune alterations at the end of the life span.
Author Keywords: Aging; Immunity; Monkey; Immune senescence; Natural killer cell; Interleukin-6; Endometriosis






A role of inhibitor of apoptosis (IAP) proteins in increased lymphocyte apoptosis in aged humans

Sudhir Gupta^,

Department of Medicine, Division of Basic & Medical Sciences 1, C-240, University of California, Irvine, CA 92697, USA

Available online 3 December 2003.

Abstract

Lymphocytes from aged humans show increased death-receptor-mediated apoptosis, which is associated with an increased and early activation of caspases. Inhibitor of apoptosis (IAP) proteins inhibit apoptosis by inhibiting activation and activity of caspases. Therefore, we examine the expression of two of the IAPs, the cIAP-2 and XIAP in lymphocytes from young and aged subjects by Western blotting. Lymphocytes from aged expressed significantly less cIAP2 whereas no difference was observed in XIAP expression between young and aged subjects. These data may suggest that decreased cIAP2 may play a role in increased apoptosis in aged humans. Possible mechanisms for the regulation of IAPs in aging are discussed.
Author Keywords: Apoptosis; Lymphocytes; T cell; IAPs; Aging; Caspases










Impact of the Hayflick Limit on T cell responses to infection: lessons from aging and HIV disease

Rita B. Effros^,

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

Available online 3 December 2003.

Abstract

Aging and HIV disease show certain immunological similarities. In both situations, control over viral infection is diminished, and there is an increase in certain types of cancer. The immune cell type responsible for controlling viral infections and cancer is the so-called CD8 or cytotoxic T cell. In elderly persons and individuals chronically infected with HIV, there are high proportions of CD8 T cells that resemble cells that reach the end stage of replicative senescence in cell culture after repeated rounds of antigen-driven proliferation. Senescent cultures are characterized by irreversible cell cycle arrest, shortened telomeres, inability to upregulate telomerase, loss of CD28 expression, and apoptosis resistance. Strategies that retard replicative senescence may, therefore, provide novel approaches to enhancing immune function during aging and HIV disease.
Author Keywords: T cells; Replicative senescence; Aging; HIV disease









The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function

Harry Dawson, Gary Collins, Robert Pyle, Vishwa Deep-Dixit and Dennis D. Taub^,

Laboratory of Immunology, Clinical Immunology Section, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA

Available online 13 December 2003.

Abstract

Elevated levels of homocysteine (Hcy) have been identified as independent risk identifiers for cardiovascular disease, cerebrovascular disease as well as for all-cause mortality. Despite the potential importance of these observations, a definitive pathological role for Hcy or its various metabolites in any of these conditions has not been established. Particularly deficient is a description of the effects of elevated levels of homocysteine on immune function. Folic acid and vitamin B12 deficiency have been independently associated with decreased immune function, the apoptosis of bone marrow hematopoietic progenitor cells and the appearance of leukocytes with hypomethylated DNA in the peripheral circulation. A specific role for Hcy or its metabolites in these processes has not been described. We have examined the effects of Hcy and its various derivatives on T cell activation, differentiation and cell viability. Our results have demonstrated that Hcy is a potent concentration-dependent T cell activator promoting cellular activation and differentiation as well as potentiating activation-induced cell death (AICD) and cellular apoptosis. Overall, Hcy appears to exert diverse effects on immune function in the circulation and within the tissue microenvironment possibly contributing to age-related immune dysfunction and disease pathology.
Author Keywords: Aging; Lymphocytes; Immunodeficiency; Homocysteine; Folate; Apoptosis; Th1; Cardiovascular disease






Effects of aging on DNA-binding activity of the E47 transcription factor in splenic B cells

Daniela Frasca^, , Diep Nguyen, Richard L. Riley and Bonnie B. Blomberg

Department of Microbiology and Immunology, University of Miami School of Medicine, 1600 N.W. 10th Ave, Miami, FL 33136, USA

Available online 4 December 2003.

Abstract

In the present paper, we have investigated the DNA-binding activity of the E2A-encoded transcription factor E47 in LPS-activated splenic B cells from young and old BALB/c mice. E47 is a key regulator of B cell differentiation and function: it binds to the E-box site, found in the regulatory regions of several B cell-specific genes (immunoglobulin (Ig), mb-1, and 5), promotes cell survival of early pre-B cells, helps to initiate Ig rearrangements, promotes class switch and is perhaps involved in somatic mutation in mature splenic and lymph node B cells. Results show that LPS-stimulated splenic B cells from old mice display decreased E47 DNA-binding activity as compared to young mice and that in splenic activated B cells only E47 homodimers bind DNA.
Author Keywords: Aging; Splenic B cells; E47 transcription factor









Thymosin ₄ promotes angiogenesis, wound healing, and hair follicle development

D. Philp^a, A. L. Goldstein^b and H. K. Kleinman<sup>, , a

a</sup> Cell Biology Section, CDBRB, National Institute of Dental and Craniofacial Research (NIDCR), NIH 30/433, Bethesda, MD 20892, USA
^b The George Washington University Medical Center, Washington, DC, USA

Available online 16 December 2003.

Abstract

New blood vessel formation is important in many physiological process, including development, wound repair, and tumor growth. In aged animals, angiogenesis is reduced resulting in poor wound healing. We have identified a novel small molecule, thymosin ₄, that promotes angiogenesis and wound repair in both normal and aged rodents. It also promotes hair growth in normal and aged rodents. It acts by increasing angiogenesis and cell migration and is currently in clinical trials for wound repair.











Determinants of plasma leptin concentration in postmenopausal women

Esther M. Brooks-Asplund^a, Carrie E. Tupper^a, Jane M. Daun^a, W. Larry Kenney^a and Joseph G. Cannon<sup>, , b

a</sup> Noll Physiological Research Center, Pennsylvania State University, University Park, PA 16802, USA
^b Department of Medical Technology and Physiology, School of Allied Health Sciences, AA-2028, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912-0100, USA

Available online 2 December 2003.

Abstract

This investigation examined the influence of hormone replacement therapy on plasma leptin concentrations in postmenopausal women and sought to determine if a relationship existed between plasma leptin, the thermoregulatory cytokine interleukin-1 (IL-1), and basal body temperature. Twenty-two women (54–71 years of age) were studied: eight were not taking hormone replacement, seven took oral estrogen only, and seven took oral estrogen plus progestin. Morning oral temperature, plasma leptin concentration, and mononuclear cell secretion of IL-1, IL-1 receptor antagonist (IL-1Ra), and soluble IL-1 receptor type II (sIL-1RII) were measured. Plasma leptin concentrations were not affected by hormone replacement therapy, but were inversely related to years since menopause (R=-0.48, P=0.02) and were proportional to IL-1 activity (the balance of IL-1/IL-1Ra secretion, R=0.69, P=0.001). Moreover, morning oral temperature was positively related to plasma leptin (P=0.03), after stratifying by progestin intake. These results support the concept that basal body temperature is regulated by a network of endocrine and immune mediators that are significantly influenced by age.
Author Keywords: Leptin; Age; Progesterone; Interleukin-1






Immunosuppression after injury in aged mice is associated with a TH1–TH2 shift, which can be restored by estrogen treatment

Elizabeth J. Kovacs^, , Lisa A. Duffner and Timothy P. Plackett

Immunology and Aging Program, Burn and Shock Trauma Institute, Department of Cell Biology, Neurobiology, and Anatomy, Department of Surgery, Loyola University Medical Center, Stritch School of Medicine, Building 110, Room 4237, 2160 South First Avenue, Maywood, IL 60153, USA

Available online 2 December 2003.

Abstract

Aged mice are less likely to survive following traumatic injury and are more immunosuppressed than young mice who sustain comparable injuries. Immunosuppression in severely injured patients is associated with a TH1–TH2 shift. Young mice had robust delayed-type hypersensitivity (DTH) responses after receiving scald or sham injury, whereas the response was diminished in aged sham-injured mice (P<0.05), and completely absent in aged burn-injured mice (P<0.01). Production of interferon- (IFN-) did not differ between splenocytes from sham-injured young and aged mice. Splenocytes from burn-injured young and aged mice yielded similar (63–68%) decreases in IFN-, relative to sham-injured mice (P<0.05). In the absence of injury, cells from aged mice produced 2-fold more interleukin-4 (IL-4) than cells from young (P<0.01). Interestingly, after burn, less IL-4 was produced by cell from young and aged mice, when compared to age-matched sham-injured animals (P<0.05). Further studies revealed that estrogen replacement in aged mice restored the post-injury DTH responses (P<0.05). Interestingly, this restoration paralleled a recovery in IFN- production by splenocytes, but not IL-4 production. Additional studies will be required to determine if age-specific therapies are needed for the treatment of all trauma patients.
Author Keywords: Immunosenescence; Hormone replacement; Lymphocytes; IFN-; IL-4; Burn injury





The usefulness of mouse breast tumor models for testing and optimization of breast cancer vaccines at old age

Claudia Gravekamp^, , Roza Sypniewska and Lieve Hoflack

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 14960 Omicron Drive, San Antonio, TX 78245, USA

Available online 9 December 2003.

Abstract

Cancer is an age-related disease and with the graying of the society, there is an increasing need to optimize cancer management and therapy for application in elderly patients. Cancer vaccines that can be applied in both prevention and therapy are potentially less toxic than chemotherapy or radiation and could, therefore, be especially suitable for older more frail cancer patients. In this study, we used syngeneic metastatic (4TO7) and non-metastatic (64pT) breast tumor models to obtain valuable information on the potential usefulness of MAGE-encoding cancer vaccines in metastatic and non-metastatic breast cancer at old age. First, we tested a mouse Mage-b DNA vaccine in young mice and found a significant preventive effect on the development of metastases. However, little effect was observed on primary breast tumors. Second, we studied tumor progression in relation to aging and found significant smaller tumors in old compared to young mice. This was associated with an increase in the percentage of CD8⁺ T cells in the inguinal lymph nodes at the site of the tumor at old age. These findings suggest that breast cancer immunotherapeutic approaches could be a valid strategy even in elderly patients.
Author Keywords: Mage-b DNA vaccine; Breast tumor models; Metastases









Protection of the elderly from pneumococcal pneumonia with a protein-based vaccine?

David E. Briles^,

Department of Microbiology, University of Alabama at Birmingham, Suite 258/11, Bevill Biomedical Research Building, 1530 3rd Avenue South, Birmingham, AL 35294-2170, USA

Available online 4 December 2003.

Abstract

Vaccines exist to protect children and adults from pneumococcal infection. The adult vaccine contains capsular polysaccharides from those pneumococci causing the vast majority of pneumococcal infection around the world. This vaccine is, however, poorly immunogenic and not as protective as would be desired. The vaccine for children is a seven-valent conjugate vaccine, which is highly protective against invasive infection and offers some protection against otitis media and pneumococcal carriage. The capsular types in the vaccine are not all appropriate for the developing world and the vaccine is too expensive for use in the developing world. As a result of these problems there have been extensive efforts to develop pneumococcal vaccines for adults and children based on cross-reactive protein antigens. The molecules used are in general virulence factors and the antibodies to them neutralize their function, thus reducing the virulence of the infecting bacteria. Studies in humans have revealed that the proteins studied are invariably immunogenic in humans, as at least low levels of antibody are seen following colonization or infection. Studies in mice have demonstrated that vaccines containing more than one of these virulence proteins are generally more protective than those involving just one. Proteins that have been studied the most in mice are pneumococcal surface protein A (PspA), PspC, PsaA, and pneumolysin. PspA has been used in human safety trials and was shown to elicit antibodies that can protect mice from otherwise fatal pneumococcal infections.
Author Keywords: Vaccine; Pneumococcal pneumonia; Protein-based vaccine






Research on aging in Iceland: future potentials

Adalsteinn Gudmundsson<sup>, , a, b, c

a</sup> Hrafnista Nursing Homes, Reykjavik, Iceland
^b University Hospital of Iceland-Reykjavik, Reykjavik, Iceland
^c University of Wisconsin Medical School, Madison, WI, USA

Available online 4 December 2003.

Abstract

Iceland is a small but prototypic western society strategically located between mainland Europe and North America. Through private and public funding, Iceland is a model in the making for opportunities in research on aging. Its ethnically and socioeconomically homogenous population served by an advanced health care system has historically been exceptionally supportive and willing to participate in both trans-sectional and cohort studies. Interdisciplinary geriatric care is well established and Iceland was on of the first countries to adapt from the US, the resident assessment instrument (RAI), which makes comparison of long-term care between countries very feasible. Among a number of biotech companies recently established in Iceland is Deocode, a leading company in the field of linking genetic variation to diseases. A major population study on interactions between age, genes and environment (AGES) was launched by the Icelandic Heart Association in 2002 through support from the NIA and the Icelandic government. Ultimately, one may expect that a cutting edge aging research in Iceland will contribute to our understanding of how to maintain a better health, independence and active participation in later life.
Author Keywords: Iceland; Aging; Aging research







Macrophage hypo-responsiveness to interferon- in aged mice is associated with impaired signaling through Jak-STAT

P. Yoon^a, K. T. Keylock^a, M. E. Hartman^b, G. G. Freund^b and J. A. Woods<sup>, , a

a</sup> Department of Kinesiology, University of Illinois, 906 S. Goodwin Avenue, Urbana, IL 61801, USA
^b Department of Animal Science, University of Illinois, Urbana, IL 61801, USA

Available online 4 December 2003.

Abstract

Since macrophages (Ms) are a first line of defense against pathogens, and are involved in both innate and adaptive immunity, understanding the impact of aging on M function is important. In the past studies, we and others have shown that aging decreases M responsiveness to classical activating signals (e.g. IFN- and lipopolysaccharide, LPS). In this study, we examined the impact of aging on M signaling through the IFN- receptor pathway. Ms from male Balb/c mice aged 2 (young) and 18–24 (old) months were purified and then stimulated with IFN-. Western blotting revealed a significant reduction (~50%) in IFN--stimulated tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1) and in Ms from aged, when compared with young mice. This reduction in phospho-STAT-1 was associated with a significant constitutive reduction (~80%) in total STAT-1 protein and a complete inhibition of STAT-1 gene expression in response to IFN- in old compared to young mice. These data may, in part, explain why classical M responses like reactive nitrogen and oxygen species generation, tumor killing and microbicidal activity are lower in Ms from aged subjects. We conclude that peritoneal Ms from aged mice have an intrinsic defect in Jak-STAT signaling which prevents them from fully responding to IFN-.
Author Keywords: Macrophage; Aging; Interferon-; STAT-1; Classical activation






Resistance to silica-induced lung fibrosis in senescent rats: role of alveolar macrophages and tumor necrosis factor- (TNF)

E. Corsini^{, , a}, A. Giani^a, S. Peano^b, M. Marinovich^a and C. L. Galli<sup>a

a</sup> Laboratory of Toxicology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy
^b RBM, Colleretto Giacosa, Italy

Available online 2 December 2003.

Abstract

The purpose of the present study was to investigate the effect of aging on silica-induced lung toxicity. In young animals silica induced a significant increase in bronchoalveolar lavage tumor necrosis factor-alpha (TNF), lactate dehydrogenase as well as in cell numbers, which correlate with increased collagen deposition and silicotic nodules formations. In old rats, however, no changes in bronchoalveolar lavage or lung parameters were observed following silica instillation. These in vivo results were also confirmed in vitro, where silica failed to induce TNF release in alveolar macrophages obtained from old animals. This defective response to silica could be explained with defective protein kinase C translocation, due to a reduction in its anchoring protein RACK-1 with aging. Overall, these data indicate that the understanding of the molecular mechanisms undelaying toxicity is crucial to define the influence of age on the toxic response and progression of the disease.
Author Keywords: Lung fibrosis; Silicosis; TNF








Post-marketing effectiveness of Prevnar [pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein)] and implications for adult immunization

Betsy Abraham-Van Parijs and Frank J. Malinoski^,

Wyeth Pharmaceutical, 500 Arcola Rd., Collegeville, PA 19426, USA

Available online 29 December 2003.

Abstract

Pneumococcal pneumonia is a significant health concern for pediatric, healthy adult, and elderly populations. The newly licensed pneumococcal 7-valent conjugate (diphtheria CRM197 protein) vaccine, Prevnar, and a second generation experimental 9-valent product have demonstrated, for the first time, a clear and significant impact on pneumococcal pneumonia in children. The potential for saccharide-conjugate vaccines to help prevent pneumococcal pneumonia in adult and elderly populations and potential barriers to the introduction of a conjugate vaccine in adults are discussed.
Author Keywords: Pneumococcal vaccine; Adult immunization; Vaccines










Alzheimer's A vaccination of rhesus monkeys (Macaca mulatta)

Sam Gandy^{, , a}, Ron B. DeMattos^b, Cynthia A. Lemere^c, Frank L. Heppner^d, Jodi Leverone^c, Adriano Aguzzi^d, William B. Ershler^e, Jinlu Dai^f, Paul Fraser^g, Peter St George Hyslop^g, David M. Holtzman^b, Lary C. Walker^h and Evan T. Keller<sup>f

a</sup> Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA
^b Washington University, St. Louis, MO, USA
^c Harvard and Brigham Medical Institutes, Women's Hospital Center for Neurological Diseases, Boston, MA, USA
^d University of Zurich, Zurich, Switzerland
^e Institute for Advanced Studies in Aging and Geriatric Medicine, Washington, DC, USA
^f Department of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
^g Centre for Research in Neurodegenerative Diseases, University of, Toronto, Ont., Canada
^h Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

Available online 29 December 2003.

Abstract

Recent preliminary data suggest that vaccination with Alzheimer's A might reduce senile plaque load and stabilize cognitive decline in human Alzheimer's disease. To examine the mechanisms and consequences of anti-A-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated A^1–42. Immunized monkeys developed anti-A titers exceeding 1:1000, and their plasma A levels were 5–10-fold higher than the plasma A levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer's A.
Author Keywords: Alzheimers; Alzheimer's vaccination; Rhesus monkey; Immunization